DUODOPA

Duodopa is a gel for continuous intestinal administration. For long-term administration, the gel should be administered with a portable pump directly into the duodenum or upper jejunum by a permanent tube via percutaneous endoscopic gastrostomy with an outer transabdominal tube and an inner intestinal tube.

Alternatively, a radiological gastrojejunostomy may be considered if percutaneous endoscopic gastrostomy is not suitable for any reason. Establishment of the transabdominal port and dose adjustments should be carried out in association with a neurological clinic.

A temporary nasoduodenal/nasojejunal tube should be considered to determine if the patient responds favourably to this method of treatment before a permanent percutaneous endoscopic gastrostomy with jejunal tube (PEG-J) is placed. In cases where the physician considers this assessment is not necessary, the nasojejunal test phase may be waived and treatment initiated directly with placement of the PEG-J.

The dose should be adjusted to an optimal clinical response for the individual patient, which means maximizing the functional ON-time during the day by minimizing the number and duration of OFF episodes (bradykinesia) and minimizing ON-time with disabling dyskinesia.

See recommendations under Dosage. Duodopa should be given initially as monotherapy. If required other medicinal products for Parkinson's disease can be taken concurrently. For administration of Duodopa only the CADD-legacy 1400 pump (CE 0473) should be used.

A manual with instructions for using the portable pump is delivered together with the pump. Treatment with Duodopa using a permanent tube can be discontinued at any time by withdrawing the tube and letting the wound heal. Treatment should then continue with oral medicinal products including levodopa/carbidopa.

Dosage:

The total dose/day of Duodopa is composed of three individually adjusted doses: the morning bolus dose, the continuous maintenance dose and extra bolus doses administered over approximately 16 hours. In addition to daytime, if medically justified Duodopa may be administered during the night.

The medicine cassettes are for single use only and should not be used for longer than 24 hours, even if some medicinal product remains. Do not reuse an opened cassette. By the end of the storage time the gel might become slightly yellow.

This does not influence the concentration of the medicine or the treatment.

Morning dose:

The morning bolus dose is administered by the pump to rapidly achieve the therapeutic dose level (within 10-30 minutes). The dose should be based on the patient’s previous morning intake of levodopa + the volume to fill the tubing. The total morning dose is usually 5-10 ml, corresponding to 100-200 mg levodopa.

The total morning dose should not exceed 15 ml (300 mg levodopa). 1 ml/hour). The dose should be calculated according to the patient's previous daily intake of levodopa. When supplementary medicines are discontinued the Duodopa dose should be adjusted.

The continuous maintenance dose is adjusted individually. It should be kept within a range of 1-10 ml/hour (20-200 mg levodopa/hour) and is usually 2-6 ml/hour (40-120 mg levodopa/hour). 4). In exceptional cases a higher dose may be needed.

7 ml/hour.

Extra bolus doses:

To be given as required if the patient becomes hypokinetic during the day. 0 ml. In rare cases a higher dose may be needed. If the need for extra bolus doses exceeds 5 per day the maintenance dose should be increased. After the initial dose setting, fine adjustments of the morning bolus dose, the maintenance dose and extra bolus doses should be carried out over a few weeks.

Monitoring of treatment:

A sudden deterioration in treatment response with recurring motor fluctuations should lead to the suspicion that the distal part of the tube has become displaced from the duodenum/jejunum into the stomach. The location of the tube should be determined by X-ray and the end of the tube repositioned to the duodenum/jejunum.

Special Populations Paediatric population There is no relevant use of Duodopa in the paediatric population in the indication of advanced levodopa-responsive Parkinson’s disease with severe motor fluctuations and hyper- /dyskinesia.

Geriatric Population There is a considerable experience in the use of levodopa/carbidopa in elderly patients. Doses for all patients including geriatric population are individually adjusted by titration. Renal/hepatic impairment There are no studies on the pharmacokinetics of carbidopa and levodopa in patients with hepatic or renal impairment.

Dosing with Duodopa is individualized by titration to optimal effect (which corresponds to individually optimized levodopa and carbidopa plasma exposures); therefore, potential effects of hepatic or renal impairment on levodopa and carbidopa exposure are indirectly accounted for in dose titration.

4). Interruption of therapy Patients should be carefully observed in case a sudden reduction of the dose is required or if it becomes necessary to discontinue treatment with Duodopa, particularly if the patient is receiving antipsychotics, see section

Drug-related undesirable effects that occur frequently with the Duodopa system include nausea and dyskinesia. Device- and procedure related undesirable effects that occur frequently with the Duodopa system include abdominal pain, complications of device insertion, excessive granulation tissue, incision site erythema, postoperative wound infection, post procedural discharge, procedural pain, and procedural site reaction.

Most of these adverse reactions were reported early in the studies, subsequent to the percutaneous endoscopic gastrostomy procedure and occurred during the first 28 days. Undesirable effects reported with Duodopa The safety of Duodopa was compared to the standard oral formulation of levodopa/carbidopa (100 mg/25 mg) in a total of 71 advanced Parkinson's disease patients who participated in a randomized, double-blind, double-dummy, active controlled study of 12 weeks duration.

Additional safety information was collected in an open-label, 12-month study in 354 patients with advanced Parkinson's disease and open-label extension studies. An analysis was performed for patients who received Duodopa in all studies, regardless of the study design (double-blind or open-label) to allow for a summary of drug-related adverse reactions.

Another analysis was performed for patients who received Duodopa or placebo gel through a PEG-J to allow for a summary of procedure-related and device-related adverse reactions in all studies, regardless of the study design (double-blind or open-label).

Drug-, Procedure- and device-related adverse reactions based on treatment emergent frequencies, regardless of causality assigned, in addition to adverse reactions identified during post-approval use of Duodopa are presented in Table 1.

Table 1. 4), Colitis ischaemic, Gastrointestinal ischaemia, Gastrointestinal obstruction, Intussusception, Pancreatitis, Small intestinal haemorrhage, Small intestinal ulcer, Large intestine perforation Gastric perforation, Gastro- intestinal perforation, Small intestinal ischaemia, Small intestinal perforation Respiratory, thoracic and mediastinal disorders Pneumonia / Aspiration pneumonia Skin and subcutaneou s tissue disorders Excessive granulation tissue General disorders and administrati on site conditions Complications of device insertione Device dislocation, Device occlusion Injury, poisoning and procedural complicatio ns Incision site erythema, Post procedural discharge, Procedural pain, Procedural site reaction Gastrointestina l stoma complication, Incision site pain, Postoperative Ileus, Post procedural complication, Post procedural discomfort, Post procedural haemorrhage a ADRs observed in clinical trials.

Frequencies assigned reflect adverse event frequencies and are regardless of causality assigned by the investigator b ADRs […]

4. In the case of suspected or diagnosed dementia with a decreased confusion threshold, the pump of the patient should be handled only by the nursing staff or a caregiver. When a cassette is about to be used, it should be attached to the portable pump and the system connected to the nasoduodenal tube or duodenal/jejunal tube for administration, according to the instructions given.

1. • narrow-angle glaucoma • severe heart failure • severe cardiac arrhythmia • acute stroke • non-selective MAO inhibitors and selective MAO type A inhibitors are contraindicated for use with Duodopa. These inhibitors must be discontinued at least two weeks prior to initiating therapy with Duodopa.

5). g. pheochromocytoma, hyperthyroidism and Cushing’s syndrome. Because levodopa may activate malignant melanoma, Duodopa should not be used in patients with suspicious undiagnosed skin lesions or a history of melanoma. 4 Special warnings and precautions for use Several warnings and precautions below are generic for levodopa and, therefore, also for Duodopa.

• Duodopa is not recommended for the treatment of drug-induced extrapyramidal reactions. • Duodopa therapy should be administered with caution to patients with severe cardiovascular or pulmonary disease, bronchial asthma, renal, hepatic or endocrine disease, or history of peptic ulcer disease or of convulsions.

• In patients with a history of myocardial infarction who have residual atrial nodal or ventricular arrhythmias, cardiac function should be monitored with particular care during the period of initial dosage adjustments. • All patients treated with Duodopa should be monitored carefully for the development of mental changes, depression with suicidal tendencies, and other serious mental changes.

Patients with past or current psychosis should be treated with caution. 5. • Patients with chronic wide-angle glaucoma may be treated with Duodopa with caution, provided the intra-ocular pressure is well controlled and the patient is monitored carefully for changes in intra-ocular pressure.

• Duodopa may induce orthostatic hypotension. 5. 7). g. agitation, confusion, coma) and increased serum creatine phosphokinase, has been reported when anti-Parkinsonian medicinal products were withdrawn abruptly. Rhabdomyolysis secondary to Neuroleptic Malignant Syndrome or severe dyskinesias have been observed rarely in patients with Parkinson’s disease.

Therefore, patients should be carefully observed when the dose of levodopa/carbidopa combinations are abruptly reduced or discontinued, especially if the patient is receiving anti-psychotics. Neither NMS nor rhabdomyolysis has been reported in association with Duodopa.

• Patients should be regularly monitored for the development of impulse control disorders. Patients and carers should be made aware that behavioural symptoms of impulse control disorders including pathologic gambling, increased libido and hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists and/or other dopaminergic treatments containing levodopa including Duodopa.

Review of treatment is recommended if such symptoms develop. • Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk of developing melanoma than the general population. It is unclear whether the increased risk observed was due to Parkinson’s disease or other factors, such as medicines used to treat Parkinson’s disease.

Therefore, patients and providers are advised to monitor for melanomas on a regular basis when using Duodopa for any indication. g. dermatologists). • If general anaesthesia is required, treatment with Duodopa may be continued for as long as the patient is permitted to take fluids and medicinal products by mouth.

If therapy has to be stopped temporarily, Duodopa at the same dose as before may be restarted as soon as oral intake of fluid is allowed. • The dose of Duodopa may need to be adjusted downwards in order to avoid levodopa induced dyskinesias.

• Periodic evaluation of hepatic, haematopoietic, cardiovascular and renal function is recommended during extended therapy with Duodopa. • Duodopa contains hydrazine, a degradation product of carbidopa that can be genotoxic and possibly carcinogenic.

5 g carbidopa. The maximum recommended daily dose is 200 ml. This includes hydrazine at up to an average exposure of 4 mg/day, with a maximum of 8 mg/day. The clinical significance of this hydrazine exposure is not known. • Previous surgery in the upper part of the abdomen may lead to difficulty in performing gastrostomy or […]

1. • narrow-angle glaucoma • severe heart failure • severe cardiac arrhythmia • acute stroke • non-selective MAO inhibitors and selective MAO type A inhibitors are contraindicated for use with Duodopa. These inhibitors must be discontinued at least two weeks prior to initiating therapy with Duodopa.

5). g. pheochromocytoma, hyperthyroidism and Cushing’s syndrome. Because levodopa may activate malignant melanoma, Duodopa should not be used in patients with suspicious undiagnosed skin lesions or a history of melanoma.